Cancers of the B cell such as lymphomas and leukemias are relatively prevalent human diseases. Of those cancers, chronic lymphocytic leukemia (CLL) is the most prevalent, with about 10,000 new cases being diagnosed each year. CLL accounts for about 30 percent of leukemias in western countries.
In addition to CLL, there are several other B cell cancers. Included among those additional B cell cancers are non-Hodgkin's lymphomas, hairy cell leukemia, plasmacytomas, plasma cell leukemia, multiple myelomas and Hodgkin's lymphomas. Similar cancers are often present in other mammalian hosts, such as the mouse, where, for example the BCL.sub.1 5B.sub.1 b cell line has similarity to CLL cell subsets.
Treatments for these cancers have varying degrees of effectiveness. For example, hairy cell leukemia, which affects relatively few people, has recently been very effectively treated with 2-chloro-2'-deoxyadenosine. A typical treatment for CLL uses chlorambucil as the usual first anti-cancer drug of choice and sometimes adds a glucosteroid such as prednisone or dexamethasone. However, patients at intermediate to high risk levels with this form of cancer have median survivals of six and two years, respectively, and those two classes of the disease constitute about 70 percent of the cases.
CLL cells proliferate quite slowly, and as a result, cytotoxic anti-cancer drugs that act at specific stages in the cell cycle and can thus act preferentially on rapidly proliferating cells, are rendered minimally effective in this disease. To date, except for a preliminary report by the inventors herein [Goodman and Piro, Blood, 78:437a (Suppl. 1) (Nov. 15, 1991)], there has been no report of inducing the proliferation of CLL cells with a chemotherapeutic agent that is pharmaceutically useful. The chemotherapeutic agent used in that work was loxoribine; 7-allyl-8-oxoguanosine.
Co-assigned U.S. Pat. No. 4,539,205 to Goodman and Weigle describes modulation of animal cellular responses with S-substituted guanine derivatives bonded 9-1' to an aldose having 5 or 6 carbon atoms in the aldose chain (ring). The cellular modulations described in that patent relate mostly to immunomodulation such as adjuvanticity in producing primary and secondary immune responses. Activity against certain neoplastic conditions is also disclosed as are T cell-replacing activity, an IL-I like activity on thymocytes, and induction of the release of lysosomal enzymes from neutrophils. The 8-substituents in those molecules have electron withdrawing inductive effects relative to hydrogen. Thus, halo, mercapto or its thioxo tautomer, acyl mercapto, alkyl sulfido, nitro, cyano, keto, halomethyl and methyleneoxy alkyl and the like were disclosed as useful, while electron donating substituents such as an amino group were found to be inactive.
In addition, co-assigned, U.S. Pat. No. 4,643,992 its continuation, U.S. Pat. No. 4,849,411, and divisional U.S. Pat. Nos. 4,948,730, 5,147,636, and U.S. patent application Ser. No. 07/945,215, filed Sep. 15, 1992, further disclose the use of derivatives of 8-hydroxyguanine (8-oxoguanine), 7-methyl-8-oxoguanine and 7-methyl-8-thioxo-guanine in modulating animal immune responses. Further results using guanine derivatives disclosed in U.S. Pat. No. 4,539,205 are also disclosed as are similar results using guanine derivatives disclosed for the first time in that application.
U.S. Pat. No. 3,798,210 to Pfleiderer describes the synthesis of 8-(1'-glycosidyl)-pteridines, including isoxanthopterin derivatives. That patent teaches the use of its compounds as the active pharmaceutical agents against specific pathogens such as malaria and tubercle bacilli, pathogenic fungi, gram-positive and gram-negative bacteria, and primarily against viruses such as herpes virus and influenza virus. Some of the compounds of the Pfleiderer patent are also useful herein, not as antibiotics as is taught in Pfleiderer, but as an immune response-enhancing agent. This use is described hereinafter.
Co-assigned U.S. Pat. No. 4,746,651 discloses the antimicrobial use of an antibiotic and a potentiating amount of a guanosine compound or isoxanthopterin as described in the above patents and those discussed hereinafter. Thus, U.S. Pat. Nos. 5,011,828 and 5,093,318 disclose immune response-enhancing guanosine derivatives having an .dbd.O, .dbd.S, .dbd.Se and .dbd.NCN groups at the 8-position of a guanine nucleoside and a hydrocarbyl or heteroatom-substituted hydrocarbyl group at the 7-position of the guanine ring. U.S. Pat. Nos. 4,880,784 and 5,166,141 disclose 7-oxa- and 7-thia-guanosines having an .dbd.O or .dbd.S group at the 8-position of the ring.